Is Tamoxifen (tamoxifen citrate) associated with an increased risk of uterine cancer, specifically endometrial cancer?

Tamoxifen and Endometrial Cancer Risk

Tamoxifen significantly increases the risk of endometrial cancer, with approximately 2-4 times higher incidence compared to non-users, particularly in postmenopausal women. 1, 2

Evidence of Increased Risk

The association between tamoxifen and uterine cancer is well-documented in multiple guidelines and the FDA label:

• The National Surgical Adjuvant Breast and Bowel Project (NSABP) data shows an incidence of endometrial adenocarcinoma of 2.20 per 1000 women-years for tamoxifen users versus 0.71 for placebo 1
• Uterine sarcoma risk is also elevated at 0.17 per 1000 women-years for tamoxifen users versus 0.0 for placebo 1
• The FDA includes a black box warning highlighting the increased risk of both epithelial endometrial cancer and uterine sarcoma 2
• In the NSABP P-1 trial, women randomized to tamoxifen had a statistically significant increase in endometrial cancer with a risk ratio of 2.48 (95% CI: 1.27-4.92) 2

Risk Factors and Patterns

The risk of endometrial cancer with tamoxifen use varies by:

• Age: Risk is significantly higher in women ≥50 years (RR = 4.01,95% CI: 1.70-10.90) compared to women <49 years (RR = 1.21,95% CI: 0.41-3.60) 1
• Duration: Risk increases with longer duration of tamoxifen use, with women taking tamoxifen for >5 years having 4.06-fold greater odds of developing endometrial cancer 3
• Menopausal status: Postmenopausal women have a substantially higher risk than premenopausal women 4
• Prior estrogen exposure: Women with previous estrogen replacement therapy (ERT) exposure have significantly higher risk when taking tamoxifen 3
• Body weight: Heavier women taking tamoxifen have a stronger risk association than thinner women 3

Mechanism

Tamoxifen has both estrogen antagonist and agonist properties, with its effects varying by tissue type. In the uterus, tamoxifen acts as a partial estrogen agonist, leading to endometrial thickening, stromal changes, polyp formation, and increased risk of endometrial hyperplasia and cancer 5.

Recent Evidence on Premenopausal Women

While historically the risk was thought to be primarily in postmenopausal women, a 2022 longitudinal cohort study of 78,320 premenopausal Korean women with breast cancer found:

• Tamoxifen users had significantly higher risk of endometrial cancer (HR 3.77,95% CI: 3.04-4.66) compared to controls 6
• Incidence of endometrial cancer was 2.01 cases per 1000 person-years among tamoxifen users 6

Clinical Recommendations

1. Baseline assessment: All women should have a baseline gynecologic assessment before starting tamoxifen 5

2. Monitoring:

   • Regular gynecologic assessments at each follow-up visit 5
   • No routine endometrial surveillance (ultrasound or biopsy) is recommended for asymptomatic women 5, 4

3. Symptom evaluation:

   • Prompt evaluation of any vaginal bleeding or spotting is essential, as most women with tamoxifen-associated endometrial cancer present with this early symptom 1, 5
   • Transvaginal ultrasound is recommended as first-line assessment for symptomatic women 5

4. Management of confirmed endometrial pathology:

   • Tamoxifen should be discontinued until cancer is fully treated 5
   • It is reasonable to resume therapy after completion of treatment for early-stage endometrial cancer 1

Risk-Benefit Considerations

When prescribing tamoxifen, the benefits of breast cancer risk reduction must be weighed against the increased risk of endometrial pathology, particularly in:

• Postmenopausal women with an intact uterus
• Women with prior estrogen replacement therapy
• Obese women
• Women requiring long-term (>5 years) treatment

These higher-risk groups may warrant closer surveillance for endometrial cancer when prescribed tamoxifen 3.